DESCRIPTION: (Applicant's Abstract) The neurotransmitter dopamine (DA) is crucial to prefrontal function, has been implicated in a variety of neurological disorders (e.g., Parkinson's Disease, schizophrenia), and may play a preferential role in working memory and higher cognitive processes. The long-term objective of this project is to understand the role of dopamine in brain function and dysfunction. This objective is embodied in a series of studies of the effects of dopamine agonists on cognition, which satisfy the two specific aims of this project. First, we propose to study the effects of dopamine agonists on cognitive performance. Cognitive neuropsychological models of prefrontal function suggest that working memory (WM) is a critical component of higher cognitive processes, and that it depends strongly on dopaminergic pathways. A series of challenge protocols will address the basic questions about the interaction of drug effects with individual differences in working memory ability; about the range of cognitive abilities that depend on neural systems affected by these drugs; and about the nature of the tasks that depend on dopamine in the prefrontal cortex. We hypothesize that the effects of dopamine agonists will be predicted by a single model; that there is an optimal level of dopaminergic neurotransmission, and that small differences in individual tuning predict the effects of drugs on behavior. Second, we propose to use a combination of drug challenge and functional neuroimaging methods to identify cortical areas mediating the cognitive effects of these drugs. While previous studies have examined either the behavioral effects of particular drugs, or the neural processes underlying particular cognitive processes, combining these methods lets us examine more directly the neural bases of drug effects on cognition. Existing studies combining these two methods validate the combination of these techniques, but do not address themselves to this basic question. We hypothesize that differences in prefrontal activation -- i.e., both direct and indirect prefrontal cortical effects of dopamine agonists -- underlie drug-related changes in performance, while other potential cortical effects of the drug will be unrelated to performance.